Diabetes refers to a disease wherein glucose level is maintained above normal range (>126 mg/dl at fasting status), or hyperglycemia, due to the malfunction of body homeostasis for various reasons. In the United States alone, 6.2% of the population (17 million) suffers from diabetes, which has many complications associated with the macro and micro vascular disease such as coronary heart disease, stroke, hypertension, neuropathy, nephropathy, or retinopathy. According to the American Diabetes Association, adults with diabetes have 2-4 times higher death rate of heart disease and chance of stroke. Each year, 12,000-24,000 people lose their sight and 30,000 people lose one or both lower limbs due to diabetes. Control of blood glucose level significantly decreases the morbidity and complications related with diabetes.
There are two types of diabetes. Type I is a disease in which the body does not produce insulin due to the destruction of β-cells and Type II is a disease in which the body does not fully utilize insulin due to the increased insulin resistance thereto. Over 90% of diabetes patients are type II.
A common treatment of diabetes is the administration of sulfonylurea drugs, such as glyburide and glimepiride, to stimulate pancreatic β-cells to produce more insulin which compensates for insulin resistance. Long term use of these insulin secretagogues, however, results in the eventual exhaustion of the β-cells and induction of more resistance at the end. Acute hypoglycemia due to temporal excess of insulin is another adverse effect of these drugs.
Biguanides, such as Metform and Phenformin, increase insulin sensitivity to a certain extent but lactic acidosis, nausea and diarrhea are reported as adverse effects to their use.
TZD (thiazolidinedione) type drugs are a more recent addition to the market. They are known to enhance insulin sensitivity by stimulation of PPARγ, peroxisome proliferators activated receptor γ, which is critical for adipocyte differentiation and the modulation of genes involved in energy storage and utilization. TZD drugs are reported to markedly enhance insulin sensitivity and obviate the occurrence of hypoglycemia, but some of them have serious liver toxicity issues. This caused Rezulin to be withdrawn from the US market in 2000. Currently, researchers are actively seeking non-TZD based drugs to avoid the liver toxicity potentially associated with the thiazolidinedione functional group. PPARα is reported to be involved in β-oxidation of the fatty acids. Ligands of PPARα, such as clofibrate and fenofibrate, are known to reduce triglyceride and LDL significantly. Since diabetes is often accompanied by obesity, dyslipidemia, atherosclerosis and high levels of LDLs which worsen the complications, efforts have been made to discover PPARα and PPARγ dual agonists which may correct the abnormalities of blood glucose and dyslipidemia at the same time. Examples of such dual agonists include JTT-501 (H. Shinkai et al, Drugs Future, 1999, 24), 2-methyl-2{4-[2-(5-methyl-2-aryloxazol-4-yl)ethoxy]phenoxy} propionic acid (Dawn A. Brooks et al, J. Med. Chem., 2001, 44, 2061-4).
Activation of PPAR δ has been demonstrated to increase HDL levels (Leibowitz, WO97/28149, August 1997). More recently, a PPAR δ selective agonist was reported to have shown a dose-related increase in serum HDL-C and concomitant decrease in LDL-C and VLDL-TG in insulin-resistant, middle-aged rhesus monkeys (W. R. Oliver et al., PNAS, v. 98, pp. 5306-5311, 2001). Activation of PPAR δ alone or in combination with the simultaneous activation of PPARα and/or PPARγ may be desirable in formulating a treatment for hyperlipidemia in which HDL is increased and LDL is lowered.
The present invention is concerned with the general structure of Formula 1, which is a new class of compounds that do not belong to the typical structure of PPARα, PPARβ/δ and PPARγ class compounds, yet which are effective in lowering blood glucose, insulin, triglycerides, fatty acids and cholesterol, and increasing HDL. Compounds of Formula 1 below have potential as a new class of drugs that has beneficial effects over current drugs and candidate materials.